The long-term goal of this research project is to elucidate the basis for the actions of the cannabinoids (CBs) at the molecular level. To this end, we are developing the elements of an understanding of the relationships between cannabinoid ligand structure; cannabinoid receptor structure; and cannabinoid receptor activation at an atomic level of detail. The research plan includes three emphases: ligand-receptor recognition, ligand-induced receptor activation/inactivation and agonist-independent activation of the CB receptors. In ligand-receptor recognition studies, we will focus on required recognition elements for ligand interaction at the CB receptors. We will infer information about the CB receptors and/or modes of binding interactions at these receptors from a correlation between experimentally determined receptor affinities and biological activities and the structural and electronic features of a series of cannabinoid ligands. At each step, our work will be aided and supplemented by collaboration with experimental medicinal chemists and pharmacologists. Compounds proposed for synthesis here have been designed to test specific hypotheses that have emerged during the current grant period. Pharmacological results from evaluation of these new compounds will be used to refine the pharmacophores we construct. These pharmacophores then will be tested in receptor mutation studies. In receptor activation studies, we will analyze the interaction of CB ligands with 3D models of the CB1 and CB2 receptors that we have developed and refined. These studies will elucidate required recognition elements and probe consequences of ligand binding. At each step, this work will be aided and supplemented by collaboration with experimental pharmacologists and molecularbiologists. In agonist-independent activation studies of the CB receptors, we will probe our models of the CBreceptors to identify interactions between residues in key regions or interactions between the receptor and its environment that may lead to agonist independent activation of the CB receptors. At each step, this work will be aided and supplemented by collaboration with experimental pharmacologists and molecular biologists. Information about cannabinoid receptor structure and binding modes of ligands will aid infundamental structure-function studies of this important class of receptors and will also aid in the design of improved therapeutic agents based on the cannabinoids.